KR100212960B1 - Complex preparation for oral use - Google Patents

Abstract

The present invention relates to an oral combination preparation, and more particularly, a omeprazole clathrate having a gastric acid secretion inhibitory activity as a first component and an antimicrobial agent that inhibits the activity of Helicobacter pylori, a causative agent of gastric ulcer recurrence, as a second component The present invention relates to an oral combination preparation effective for effectively treating gastrointestinal diseases caused by excessive secretion and infection of Helicobacter pylori.

Description

Oral combinations

The present invention relates to an oral combination preparation, and more particularly, a omeprazole clathrate having a gastric acid secretion inhibitory activity as a first component and an antimicrobial agent that inhibits the activity of Helicobacter pylori, a causative agent of gastric ulcer recurrence, as a second component The present invention relates to an oral combination preparation effective for effectively treating gastrointestinal diseases caused by excessive secretion and infection of Helicobacter pylori.

In general, the treatment of gastric ulcer has been dependent on a single component that inhibits gastric acid secretion, but the recurrence rate was high when treated with a gastric acid secretion inhibitor of this single component. In order to determine the cause of recurrence of gastrointestinal diseases, researches have been continuously conducted. Among these studies, the causative agent of gastric ulcer disease has recently been reported as helicobacter pylori in the gastric mucosa.

As a result of studies on effective treatment of Helicobacter pylori infection, U.S. Patent No. 5,093,342 discloses a method of prescribing omeprazole alone, and International Patent Publication No. 92-04898 discloses antimicrobial agents amoxicillin and omeprazole. A method of mixing and prescribing is disclosed. However, antimicrobial agents can not effectively remove the Helicobacter pylori because the activity is sharply lowered in the stomach (胃).

In addition, International Patent Publication No. 93-21920 discloses a method for enhancing the activity of an antimicrobial agent such as benzyl penicillin, erythromycin, clarithromycin, and the like by combining omeprazole with an antimicrobial agent to suppress gastric acid secretion and increase acidity. Increasing the concentration. However, this method has a problem of taking an excessive amount of the drug, and in order to keep the activity of the antimicrobial agent continuously high, it is necessary to continuously take an excessive amount of the drug several times a day, and the formulation itself is manufactured by a general manufacturing method. It is not effective. In addition, omeprazole administered in combination with an antimicrobial agent is also very unstable in acid, so when administered to a patient in such a manner, it is obvious that the drug cannot be properly exhibited.

In general, omeprazole is relatively stable in the presence of an alkaline substance, but has a characteristic of rapidly deactivating upon contact with a substance other than the alkaline substance, for example, excipients or other drugs. Therefore, U.S. Patent No. 5,399,700 proposes a method of stabilizing omeprazole by enclosing an acid labile compound such as omeprazole with cyclotextine, and in this method, omeprazole is contained in the cavity of cyclotextine to affect the external environment. A very stable formulation was prepared, and the omeprazole clathrate contained in cyclotextine has a higher dissolution rate in the intestine than the unmemored omeprazole. It is absorbed by

Therefore, in the present invention, as a result of research efforts to solve the problems appearing in the co-administration of an acid labile antibacterial agent and omeprazole, omeprazole is contained in cyclotextine to be easily eluted in the intestine, and the omeprazole clathrate is a conventional enteric coating machine To prepare a coated omeprazole clathrate, which is stable to gastric acid by zero entrapment, and to prepare a coating coated with an antimicrobial agent having a helicobacter pylori removal action separately with an enteric coating base, and formulated it together in one dosage form. Omeprazole clathrate and antimicrobial coatings are acid-stable, so they can safely reach the intestine without decomposing into the stomach. Once the intestine enters the enteric coating base, which coats the two drugs, Omeprazole clathrate with high dissolution rate rapidly enters the small inlet. The present invention was completed by paying attention to the fact that absorbance lowers the acidity, and then the antimicrobial agent is absorbed with a time difference, thereby maximizing the antimicrobial activity of the antimicrobial agent and completely eliminating Helicobacter pylori.

Accordingly, an object of the present invention is to provide an oral combination preparation having both gastric acid secretion inhibition and Helicobacter pylori removal.

Hereinafter, the present invention will be described in detail.

The present invention is a combination preparation for treating the gastrointestinal tract consisting of an omeprazole and an antimicrobial agent having the ability to inhibit Helicobacter pylori, the omeprazole is an omeprazole clathrate coated with an enteric coating base, the omeprazole clathrate covered with cyclodextrin, An antimicrobial agent having the capability is characterized by an oral combination formulation containing a coating coated with an enteric coating base.

Referring to the present invention in more detail as follows.

The present invention relates to an oral complex preparation containing an omeprazole clathrate contained in a cyclodextrin and an antimicrobial agent having a helicobacter pylori inhibitory ability, respectively, coated with an enteric coating base, and containing the same. It is characterized by maximizing the antimicrobial activity of the antimicrobial agent by allowing the omeprazole clathrate to be released from the small intestine and then releasing the antimicrobial agent having the ability to inhibit Helicobacter pylori.

The omeprazole clathrate used in the present invention is a clathrate encapsulated with a cyclodextrin prepared by US Pat. No. 5,399,700.

In addition, the antimicrobial agent having a Helicobacter pylori removal action used in the present invention, Cephaclo (Cefaclor), Separexin (Cephalexin), Cefotaxime, Cefuroxime, Azithromycin (Azithromycin), Doxy It is a single or a mixture of two or more selected from cyclcycl (Doxycyclin), Ofloxacin (Ofloxacin) and cycloproxacin (Ciprofloxacin). Particularly preferred among them is sepaclo, cefuroxime and cycloproxacin, which are used alone or in combination of two or more thereof.

The combination preparation of the present invention is a time delay drug release delaying agent that first makes a condition that can maximize the antimicrobial activity of the antimicrobial agent by the action of omeprazole, and then acts as a delayed drug release delaying agent to allow the antimicrobial agent having the ability to inhibit Helicobacter pylori, The coating base of the omeprazole clathrate melts at pH 5 so that the omeprazole is rapidly absorbed at the inlet of the small intestine, and the coating base coating the antimicrobial system at pH 5.5 is melted to absorb the antimicrobial agent.

The time difference drug release delay can be selected according to the coating base, in the present invention is a coating base commonly used in the present invention, cellulose acetate phthalate (CAP), methacrylic acid copolymer, methacrylic acid ester copolymer, hydroxypropyl methyl cellulose phthalate (HPMCP), polyvinylacetate phthalate (PVAP), shellac, alginic acid, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol and polyvinylpyrrolidone, or the like Use by mixing.

Absorption of general drugs occurs mostly in the small intestine, and thus, when the enteric coating agent is properly used, very effective bioavailability can be obtained. In the coating base, CAP is dissolved at pH 6.0 or higher, Eudragit L, a methacrylic acid copolymer, is dissolved at pH 6.0 and Eudragit S is at pH 7.0, HPMCP is dissolved at pH 5.0 to 5.5, and PVAP is pH Melting around 5.5. In addition, since the small intestine maintains a pH of 5.0 to 6.0, the coating base containing the omeprazole may be dissolved at the inlet of the small intestine, so that the coating base may be properly mixed to adjust the pH range in which the coating base may be dissolved. Thus, the desired time difference drug release delaying agent can be prepared.

Referring to the production method of the composite preparation according to the present invention in more detail.

First, omeprazole is coated by a conventional coating method using the enteric coating base to prepare an omeprazole clathrate. In addition, a drug containing an antimicrobial agent having a separate Helicobacter pylori removal activity as an active ingredient is formulated together with the omeprazole clathrate as a single drug.

The daily dosage of omeprazole and antimicrobial agent in the co-formulations of the present invention for adult patients is about 0.7 to 500 mg, preferably about 7 to 100 mg for omeprazole, calculated as free base, and for the antimicrobial agent that suppresses Helicobacter pylori It is somewhat different depending on the antimicrobial agent used as about 1 to 5,000 mg, for example, 750-1500 mg is preferable for Sephaclo.

The combination preparation of the present invention as described above contains an antimicrobial agent that inhibits omeprazole clathrate and Helicobacter spurs at the same time, and also, as a delayed drug release delaying agent, omeprazole is first absorbed into the small intestine so that the antimicrobial agent can express maximum activity. It is characterized by maximizing the antimicrobial activity because it is designed to absorb conditions and subsequently absorb the antimicrobial system.

Hereinafter, the present invention will be described in more detail based on the following examples, but the present invention is not limited by the examples.

Example 1

1) Coating Antimicrobial Granule Manufacturing

The components were homogeneously mixed and placed in a granulation apparatus, thereby preparing granules using 95% ethanol (80 ml) in which 5 g of hydroxypropyl cellulose was dissolved as a binder. The antimicrobial granules were coated by spraying a solution prepared by granulating the prepared granules with a 35 mesh network and dissolving hydroxypropylmethylcellulose phthalate (HPMCP 55; 15 g) in 95% ethanol (200 mL).

2) Preparation of Complex Tablets

The coating antimicrobial granules prepared above (300g), omeprazole clathrate (160g), crystalline cellulose (35g), sodium glyconate starch (20g) and magnesium stearate (5g) homogeneously mixed and then tableted in a tablet machine 520 mg tablets were prepared.

3) Coating of composite tablet

The composite tablet was coated in a coating pan of 30mg of hydroxypropylmethylcellulose phthalate (HPMCP-50).

Example 2

Coated tablets were prepared in the same manner as in Example 1, except that cefuroxime tablets were used as antimicrobial agents.

Example 3

Coated tablets were prepared in the same manner as in Example 1 except that Sephaclo tablets were used as an antimicrobial agent.

Example 4

In the same manner as in Example 1 to prepare an antimicrobial granule, prepared granules (300g) and omeprazole (20g), anhydrous calcium dihydrogen phosphate (25g), crystalline cellulose (40g), starch glyconate (30g) and Magnesium stearate (5 g) was mixed homogeneously to prepare a tablet of 420 mg per well. The prepared tablets were coated with 20 mg of hydroxypropylmethylcellulose phthalate (HPMCP-50) in a coating pan.

Example 5

Coated tablets were prepared in the same manner as in Example 4, except that cefepuroxime tablets were used as antimicrobial agents.

Example 6

Coated tablets were prepared in the same manner as in Example 4, except that Sephaclo tablets were used as an antimicrobial agent.

Example 7

Antimicrobial granules were prepared in the same manner as in Example 1. Separately, homogeneously mix omeprazole clathrate (160g), mannitol (20g), corn starch (15g) and sodium starch glycolate (20g) to combine 95% ethanol (80ml) containing 5g of hydroxypropylcellulose. The omeprazole granules were prepared by zero, and the omeprazole granules were coated by spraying a solution made by dissolving omeprazole granules in a 35 mesh network and dissolving hydroxypropylmethylcellulose phthalate (HPMCP-50; 20 g) in 95% ethanol (200 ml). Prepared. 300 mg and 240 mg of the antimicrobial agent granules and the coated omeprazole granules prepared above were put into hard gelatin capsules to form capsules.

Comparative Example 1

A composite tablet was prepared in the same manner as in Example 1, but was not coated with hydroxypropylmethyl cellulose phthalate, which is an enteric coating base when preparing antimicrobial granules.

Comparative Example 2

Only the coated antimicrobial agent granules of 1) in Example 1 were prepared, and 300 mg of the coated antimicrobial granules were put into hard gelatin capsules to prepare capsules.

Comparative Example 3

In the preparation of the antimicrobial agent granules of Example 1 to 1), the antimicrobial agent was not coated with hydroxypropyl methyl cellulose phthalate, and only the uncoated antimicrobial agent was added to 280 mg of granules in hard gelatin capsules to prepare a capsule.

Experimental Example

Determination of Helicobacter Pylori

Thirty-six Helicobacter pylori positive patients were administered the formulations prepared in Examples and Comparative Examples for 14 days and the Helicobacter pylori removal rate was measured. Eradication of H. pylori was determined by the [ ¹⁴ C] urea breath test. In this case, eradication means Helicobacter pylori removal rate after one month of treatment.

The eradication rate of the measured Helicobacter pylori is shown in Table 1 below.

As shown in Table 1, the time-release drug release delaying agent according to the present invention shows a much higher elimination rate of Helicobacter pylori, which proves the usefulness of the present invention, and also, as described above, rapidly absorbs omeprazole first in the small intestine. By lowering the acidity of the secondary to ensure that the antimicrobial agent is stably absorbed by the second to maximize the activity of the antimicrobial agent can be very high eradication rate of Helicobacter pylori.

Claims (3)

In the combination preparation for the treatment of the gastrointestinal tract consisting of an omeprazole and an antimicrobial agent having a halybacter pylori inhibitory ability, the omeprazole is an omeprazole clathrate in which an omeprazole clathrate covered with a cyclodextrin is loaded with an enteric coating agent, and the helicobacter spurry inhibiting ability Antimicrobial agent having an oral complex preparation, characterized in that the coating is coated with an enteric coating agent. According to claim 1, wherein the antimicrobial agent having a helicobacter pylori inhibitory ability is selected from sepaclo, ceparexin, cefotaxime, cefuroxime, azithromycin, doxycycline, oproxacin and cycloproxacin, or Oral combinations, characterized in that two or more. The method of claim 1, wherein the enteric coating base is cellulose acetate phthalate (CAP), methacrylic acid copolymer, methacrylic acid ester copolymer, hydroxypropyl methyl cellulose phthalate (HPMCP), polyvinylacetate phthalate (PVAP), shellac Oral complex, alginic acid, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, or the like.